Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 285, Issue 1, Pages H259-H269Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.01028.2002
Keywords
calcium; adenine nucleotide translocator; membrane potential; cytochrome c; ATP-dependent channel; palmitic acid; palmitoyl-coenzyme A
Funding
- NHLBI NIH HHS [P50 HL-52319] Funding Source: Medline
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Fatty acids accumulate during myocardial ischemia and are implicated in ischemia-reperfusion injury and mitochondrial dysfunction. Because functional recovery after ischemia-reperfusion ultimately depends on the ability of the mitochondria to recover membrane potential (Deltapsi(m)), we studied the effects of fatty acids on Deltapsi(m) regulation, cytochrome c release, and Ca2+ handling in isolated mitochondria under conditions that mimicked aspects of ischemia-reperfusion. Long-chain but not short-chain free fatty acids caused a progressive and reversible (with BSA) increase in inner membrane leakiness ( proton leak), which limited mitochondrial ability to support Deltapsi(m). In comparison, long-chain activated fatty acids promoted 1) a slower depolarization that was not reversible with BSA, 2) cytochrome c loss that was unrelated to permeability transition pore opening, and 3) inhibition of the adenine nucleotide translocator. Together, these results impaired both mitochondrial ATP production and Ca2+ handling. Diazoxide, a selective opener of mitochondrial ATP-dependent potassium (K-ATP) channels, partially protected against these effects. These findings indicate that long-chain fatty acid accumulation during ischemia-reperfusion may predispose mitochondria to cytochrome c loss and irreversible injury and identify a novel cardioprotective action of diazoxide.
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